3'-Azido-3'-deoxythymidine (AZT) is the only drug which is commercially available for the treatment of the acquired immune deficiency syndrome (AIDS) or symptomatic advanced AIDS-related complex (ARC). AZT inhibits the human immunodifficiency virus reverse transcriptase.
The main toxic affect of AZT in patients receiving the drug is severe anemia, often associated with megaloblastic bone marrow (Yarchoan, et al., Lancet, 1986, 1:575.
AZT was found to consistently inhibit granulocyte macrophage colony forming cells and erythroid burst-forming cells in dose-dependent fashion in vitro (Sommadossi and Carlisle, Antimicrobial Agents Chemo., 1987, 31:453-454). The authors concluded that since prolonged AZT therapy will probably be required by an AIDS patient, such patients will be subject to increased myelosuppression leading to increased risk of opportunistic infections.
In studies carried out in vitro to "rescue" human bone marrow progenitor (HBMP) cells using potential rescue agents, Sommadossi, et al., found that uridine and cytidine could reverse the toxic effect of AZT in HBMP cells.
While uridine is able to reverse the toxic effect of AZT on HBMP cells in vitro, unfortunately, uridine is deleterious to humans when given in vivo. When uridine is administered to a patient in an intermittant schedule, it is rapidly eliminated from the plasma. Continuous infusion of uridine is associated with rapid and potentially dangerous rises in body temperature. (See van Groeninger, et al., Cancer Treatment Rept., 70:745-750, 1986.)
The acyclouridine 5-benzylacylouridine (BAU) is an inhibitor of the enzyme uridine phosphorylase which is responsible for the cleavage of uridine to uracil. (See Niedzwicki, et al., Biochem. Pharmacol., 1982, 31:1857-1861). BAU also inhibits the cleavage of the antineoplastic 5-fluoro-2'-deoxyuridine (Fd Urd) used in cancer chemotherapy because of its inhibition of the action of uridine phosphorylase (See Chu, et al., Cancer Res., 1984, 44:185256.)
It has been found that concomitant administration of BAU to animals receiving AZT reduces the severity of AZT-induced anemia. None of the animals treated with a combination of BAU/AZT developed severe suppression of hemoglobin or hematocrit. Administration of BAU also produced a rise in the reticulocyte count, hemoglobin and hematocrit of animals which had previously been made anemic by administration of AZT.